The field of the invention is modulation of the immune response of a mammal infected with an infectious agent.
Numerous bacterial, viral, and parasitic infections of mammals have two phases of infection: an acute phase during the early stages of the infection, sometimes followed by a prolonged chronic phase having a finite or indefinite duration. The ability of an infectious agent to establish a chronic infection in a mammalian host depends to a significant extent on the capacity of the host immune response to eliminate the infecting organism from the host in the early stages of the infection. The specific immune mechanisms responsible for eliminating the infectious agent from the host differ depending on the infectious agent. In the case of viral and some parasitic infections, the infectious agent-eliminating activity of cytotoxic T lymphocytes is believed to comprise a pivotal component of the host immune response for mediating the elimination of these agents from the host.
The components of a mammalian immune system to which mammalian immune response activities can be attributed include, but are not limited to, antibody molecules, complement molecules, B lymphocytes, T lymphocytes, cytotoxic T lymphocytes, helper T cells, suppressor T cells, immunosuppressive lymphocytes, cytokine-secreting lymphocytes, other non-cytotoxic lymphocytes, macrophages, neutrophils, mast cells, basophils, eosinophils, monocytes, and the like. Induction or replication of the host immune activities leading to complete elimination of an infectious agent from a mammalian host is the paradigm for a clinical treatment for infection by a infectious agent.
In the course of infections with bacteria and some parasites, elimination from a host of an infectious agent causing an acute infection has traditionally been accomplished using antibiotics which serve as relatively selective poisons for the infectious agent. Antibiotic treatment has been less successful in the case of chronic bacterial infection. More recently, clinical efforts have focused on modulating the host immune system in an attempt to eliminate infectious agents causing chronic infections in cases wherein indolence of the host immune system contributes to persistence of the infectious agent. Specific immune modulation using substances such as interferons alpha, beta, and gamma has been attempted, and in a minority of cases beneficial results have been observed.
When an infection becomes chronic, the infection may be controlled by a persistent host immune reaction to the infectious agent. Certain herpes viruses, for example, remain latent only in the context of host immune competence. Immunosuppressive therapy used, for example, in organ transplant recipients permits latent herpes virus to become reactivated. Thus, loss of immune competence in response to steroid and cyclosporin A administration to a human patient having a latent HHV-6 infection permits recrudescence of HHV-6. The result of HHV-6 reactivation includes viral pneumonia and bone marrow suppression. In addition, the high incidence of non-Hodgkins B cell lymphomas among humans infected with the AIDS virus (HIV-1) demonstrates that pathogenicity attributable to chronic Epstein-Barr virus infections becomes active as T cell competence is lost. Thus, reactivation of pathogenicity attributable to an otherwise non-pathogenic chronic infection which is effected by suppression of the host""s immune competence may have deleterious effects on the host.
Several microbial infectious agents cause disease in a mammalian host predominantly by eliciting a host immune response which is ineffective in eliminating the infectious agent from the host, but is effective in damaging or destroying host tissues. One such virus which functions in this manner is the AIDS virus, HIV-1. HIV-1 mediates destruction of helper T lymphocytes in HIV-1-infected humans, but the mechanism of cellular destruction has not been unequivocally defined. Although helper T cells are destroyed in culture by syncytium formation, the presence of multinucleated T cells in patient samples has not been reported. This suggests that in vivo syncytium formation is a rare event. It is known that patients infected with HIV-1 develop a strong cytotoxic response to the virus, and that this response persists throughout the course of the infection. It is also known that at least some of the T cell loss characteristic of AIDS is the result of the death of CD4-bearing T cells which express viral antigens within the context of MHC class I molecules. The death of these cells is mediated by the immune system in the infected individual.
HTLV-I, another human retrovirus, does not directly damage host cells. Patients chronically infected with HTLV-1 frequently exhibit a slowly developing neurological disease, namely HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is clinically and histopathologically similar to the human autoimmune disease, multiple sclerosis (MS).
In humans afflicted with MS, neural elements are lost, apparently due to the immune reactivity of the patient to viral antigens in the neuropil. It has been suggested that MS has an infectious etiology. Although several viruses have been suggested to be the pathogenic trigger for the development of MS, recent experimental evidence strongly suggests that human herpesvirus 6 (HHV-6) may be the infectious agent ultimately responsible for development of MS in humans. Replicating HHV-6 has been identified in MS plaques (Challoner et al., 1995, Proc. Natl. Acad. Sci. USA 92:7440-7444). Furthermore, the majority of humans having the relapsing-remitting form of MS exhibit evidence of an immune reaction to acutely replicating HHV-6 (Soldan et al., 1997, Nature Med. 3:1394-1397). These observations suggest that MS, which has long been classified as an autoimmune disease, may result from chronic infection of a human with HHV-6. If this is true, a human afflicted with MS would benefit from suppression of the immune response to the presence of HHV-6 in the human.
Certain chronic bacterial and protozoal infections also mediate disease in a mammalian host by inducing persistent host immune reactivity coupled with ineffective elimination of the infectious agent from the host. For example, Mycobacterium tuberculosis is a slow growing organism which causes tissue destruction primarily via the host autoimmune response. Similarly, the protozoan Leishmania donovani is itself relatively non-pathogenic, but a persistent host immune reaction to infection results in severe disease. Lymphatic filariasis leads to partial occlusion of the lymph channels, but the contribution of the persistent ineffective immune reaction to the parasite is also responsible for the loss of lumen patency with the resulting disfiguring elephantiasis. Mammalian infection by Leishmania braziliensis frequently leads to severe mutilating facial lesions which appear years after the original facial lesion has healed. The severe lesions are caused by repeated attempts by the immune system to destroy small numbers of the parasite remaining in the host. Similarly, parasites such as Schistosoma mansoni cause scarring of the hepatic portal tracts by inducing a persistent immune reaction to parasites dwelling within the liver. The immune reaction does not clear the infection, circulatory difficulties result, and life threatening cirrhosis with portal hypertension may ensue.
Perhaps the most illustrative example of a class of infectious agents that are intrinsically non-pathogenic in the absence of a persistent immune response is hepatitis B virus (HBV). Most individuals who become infected with HBV exhibit few clinical symptoms and eliminate the virus from their system within several weeks following exposure. About 10% of acutely HBV-infected individuals develop chronic infection. The factors which predispose individuals to chronic infection are largely unknown. HBV is ubiquitous, and the worldwide population of chronically HBV-infected individuals has been estimated by the World Health Organization at approximately 350 million. A large percentage of patients chronically infected with HBV develop life threatening cirrhosis and primary hepatocellular carcinoma as a direct result of the daily assaults on the liver by the immune system in an attempt to clear the virus.
The mechanisms ultimately responsible for HBV-mediated cirrhosis are immunopathological. Liver injury does not result directly from infection with HBV. This statement is supported by the finding that up to 70% of the hepatocytes in the liver of chronically-infected human patients harbor virus even though clinical evidence of hepatitis may be mild (Ray, 1978, Hepatitis B virus antigens in tissues, University Park Press, Baltimore, pp 49-68). Furthermore, results of experiments investigating the interaction of HBV and host cells, both in vitro and in vivo, indicate that the virus has no detectable cytotoxic or cytolytic activity. HepG2 cells have been shown to express HBV after transfection with no apparent alteration in cellular function (Roingeard et al., 1990, Hepatology 11:277-285). Recent studies employing immunocompetent transgenic mice comprising the HBV genome have shown that none of the viral antigens possess direct cytotoxic potential. Although all of the principal HBV proteins were detected in liver cells, or were present in the circulation in these mice, no evidence of cytotoxicity of these cells was observed (Araki et. al., 1989, Proc. Natl. Acad. Sci. USA 86:207-211; Farza et. al., 1988, J. Virol. 62:4144-4152).
Acute HBV infection in humans results in a vigorous anti-virus host immune response. All of the viral proteins, including the viral surface protein (HBsAg) and the nucleocapsid (core, HBcAg), provoke the production of specific immunoglobulins. Vaccination trials have proven that anti-viral antibody is critical in preventing de novo HBV infection, but that the humoral component of the immune response is of minimal utility for controlling established infection (Krugman et al., 1994, xe2x80x9cHepatitis B vaccinexe2x80x9d, In: Vaccines, Plotkin et al., eds., W. B. Saunders, Philadelphia; Gelfand, 1974, Postgrad. Med. 55:263-264; Good et al., 1960, Am. J. Med. 29:804-810). In addition, the concentration of anti-HBsAg antibodies falls to undetectable levels in the majority of chronically infected patients, further suggesting the lack of utility of these antibodies in modulating chronic HBV infection (Gerlich, 1993, In: Viral Hepatitis: Scientific Basis and Clinical Management. Zukerman et al., eds., Churchill Livingstone, Edinburgh, UK, pp 83-114). The role of the cellular component of immune defense is not so benign.
HBV-driven hepatocellular necrosis in chronically infected individuals is the result of immune cytotoxic T cells which react with viral antigens which are presented in conjunction with host MHC class I molecules on the surface of infected hepatocytes. Host immune control of the virus is not only ineffective, but is actually detrimental to a chronically infected host. The remissive/exacerbative nature of HBV-associated liver disease in chronically infected patients probably results from variations in host immune reactivity, rather than from variability in viral antigen expression. Such host variability has been suggested to result from changes in the concentration of MHC class I antigen expression on the surface of HBV-infected hepatocytes, and is the rational basis for the clinical use of alpha- and beta-interferons to treat chronic HBV infections.
The principles of oral tolerance therapy have been successfully applied to the treatment of a number of human autoimmune diseases. Preliminary results from Phase III trials of such therapies for treatment of multiple sclerosis and for treatment of rheumatoid arthritis have been reported (Weiner et. al., 1993, Science 259:1321-1324; Trentham et. al., 1993, Science 261:1727-1730). In additional, the efficacy of oral tolerance therapy has been demonstrated in animal models of allograft rejection and type II diabetes (Hancock et. al., 1993, Transplantation 55:1112-1118; Bergerot et al., 1994, J. Autoimmun. 7:655). Oral tolerance therapy has never been attempted for treatment of viral, bacterial, or parasitic infections because such endeavors were considered counterproductive and contraindicated in view of the clinician""s primary goal of clearing the infectious agent from the patient.
The immune response of a mammalian host to infection by an infectious agent may result in elicitation of an immune response to tissue antigens normally expressed by the host. By way of example, a known reaction to infection of a human by a group B hemolytic Streptococcus species is development of rheumatic fever. One or more specific streptococcal antigens stimulate production of a component of the host immune response which recognizes not only the infecting bacterium, but also antigens expressed by normal tissues present in the heart and joints of the patient. With prolonged infection, such as that which occurs in the absence of effective antibiotic treatment of the bacterial infection, the host immune system attacks normal tissues, and heart valvular defects ensue from tissue scarring mediated by the immune response. Furthermore, the patient develops arthritis, due to the response of the same component(s) of the immune system to tissues in the joints of the patient.
A similar set of disease manifestations has been reported following Streptococci mutans infection of humans secondary to dental treatment. S. mutans is a constituent of the normal flora of the oropharynx, and is a causative agent of dental caries. The trauma associated with dental care frequently results in the mechanical transmission of the bacterium to the patient""s circulation, whereby a focal infection may result. As with infection by group B hemolytic Streptococcus bacteria, one or more components of the immune system developed against the infectious agent begin destroying normal tissues, and a pathological condition results.
Parasitic diseases represent additional examples of the class of diseases which elicit a destructive autoimmune response in a mammalian host. For example, infection of a human by Onchocera volvulus, the causative agent of xe2x80x9criver blindness,xe2x80x9d elicits production of antibodies which are cross-reactive with a protein normally found in the human retina. In humans infected with Trypanosoma cruzi, the antigen designated FI-160 elicits production of antibodies which cross-react with a protein present in the central nervous system. Thus one of the disease presentations of T. cruzi is an immune-mediated destruction of the neural plexus. South American Sleeping. Sickness, also designated Chagas disease, is caused by infection of a human by T. braziliensis, which elicits immune-mediated destruction of cardiac and neural tissues.
There is a critical need for methods and compositions which are useful for modulating the undesirable autoimmune responses exhibited by mammals infected with viral, bacterial, and parasitic agents. The current invention is useful for preventing the life-long disabilities which result from these infections.
The invention relates to a method of modulating an immune response in a mammal infected with an infectious agent, the method comprising transmucosally administering a composition to the mammal. The composition comprises an epitope which is located in close proximity to the immune response in the mammal. Following administration of the composition to the mammal, the immune response is modulated. The mammal may be chronically infected with the infectious agent.
In one embodiment of the method of the invention, the infectious agent comprises an antigen which comprises the epitope. In this case, the composition may comprise the antigen.
In another embodiment of the method of the invention, the mammal comprises an antigen which comprises the epitope. In this case, the antigen may be one which reacts with a component of the immune system of the mammal only when the mammal is infected with the infectious agent. By way of example, the component may be selected from the group consisting of an antibody molecule, a complement molecule, a B lymphocyte, a T lymphocyte, a helper T lymphocyte, a suppressor T lymphocyte, a cytotoxic T lymphocyte, an immunosuppressive lymphocyte, a cytokine-secreting lymphocyte, a non-cytotoxic lymphocyte, a macrophage, a neutrophil, a mast cell, a basophil, an eosinophil, and a monocyte.
In another aspect of the method of the invention, the mammal is a human.
In yet another aspect of the method of the invention, the composition further comprises a second molecule selected from the group consisting of an antibiotic, an antiviral compound, an antiparasitic compound, an anti-inflammatory compound, an immunosuppressant, and a synergist. By way of example, the second molecule may be selected from the group consisting of lamivudine, a bacterial lipopolysaccharide, an immunoregulatory lipoprotein, a peptide covalently linked to tripalmitoyl-S-glycarylcysteinyl-seryl-serine, a steroid, cyclosporin A, AZT, ddC, ddI, and 3TC.
In still another aspect of the method of the invention, the infectious agent is selected from the group consisting of a bacterium, a virus, and a parasite. By way of example, the infectious agent may be selected from the group consisting of hepatitis B virus, hepatitis C virus, parvovirus B19, Borna disease virus, HIV, HTLV-1, Mycobacterium tuberculosis, a group B hemolytic Streptococcus bacterium, S. mutans, Trypanosoma cruzi, Leishmania donovani, Onchocerca volvulus, T. braziliensis, and S. mansoni. 
In another aspect of the method of the invention, the immune response is selected from the group consisting of an autoimmune reaction, a humoral immune response, and a cellular immune response. By way of example, the autoimmune reaction may selected from the group consisting of a humoral immune response comprising production of an antibody which cross-reacts with a tissue antigen of the mammal, a humoral immune response comprising production of an immunosuppressive factor, a cellular immune response comprising production of a cytotoxic cell which specifically induces cell death in a tissue of the mammal, and a cellular immune response comprising production of a lymphocyte which secretes an immunosuppressive factor.
In still another aspect of the method of the invention, transmucosal administration of the composition is accomplished by a route of administration selected from the group consisting of oral, enteral, intranasal, pulmonary, and colonic.
In other embodiment, the method of the invention further comprises administering to the mammal a composition comprising a second molecule selected from the group consisting of an antibiotic, an antiviral compound, an antiparasitic compound, an anti-inflammatory compound, an immunosuppressant, and a synergist. By way of example, the second molecule may be selected from the group consisting of lamivudine, a bacterial lipopolysaccharide, an immunoregulatory lipoprotein, a peptide covalently linked to tripalmitoyl-S-glycarylcysteinyl-seryl-serine, a steroid, cyclosporin A, AZT, ddC, ddI, and 3TC.
The invention also relates to a composition for modulating an immune response in a mammal infected with an infectious agent, the composition comprising an epitope which is located in close proximity to the immune response in the mammal.